Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1

PPARgamma has been extensively studied for the past decade mainly due to its central role in promoting and maintaining the adipocyte phenotype. To date, three PPARgamma isoforms have been described in man. Here we show the presence of a fourth PPARgamma promoter with its cognate mRNA initiating at exon 1, as evidenced by primer extension analysis. The presence of a putative responsive element (RORE) for RORalpha, a representative of the ROR/RZR Orphan Receptor superfamily, in the novel promoter was investigated. By gelshift experiments and site-directed mutagenesis we show that this RORE specifically binds the RORalpha1 isoform. We further demonstrate that overexpression of RORalpha1, but not the RORalpha2 and RORalpha3 isoforms, induced a 40-fold increase in promoter activity in transient transfection assays in various cell lines. Considering the strong transcriptional activation it is likely that RORalpha1 forms a part of the multifactorial regulatory mechanisms that control expression of the human PPARgamma gene.